CARING FOR THE
CRITICALLY ILL PATIENT
Delirium as a Predictor of Mortality
in Mechanically Ventilated Patients
in the Intensive Care Unit
E. Wesley Ely, MD, MPH
Ayumi Shintani, PhD, MPH
Brenda Truman, RN, MSN
Theodore Speroff, PhD
Sharon M. Gordon, PsyD
Frank E. Harrell, Jr, PhD
Sharon K. Inouye, MD, MPH
Gordon R. Bernard, MD
Robert S. Dittus, MD, MPH
I
N THE UNITED STATES, 55 000 PA-
tients are cared for daily in more than
6000 intensive care units (ICUs).1
The most common reason for ICU
admission is respiratory failure and the
need for a mechanical ventilator.2 Al-
though hospital mortality for such pa-
tients ranges from 30% to 50%,3 only
16% of patients receiving mechanical
ventilation die directly of respiratory fail-
ure.4 In fact, nonpulmonary acute or-
gan dysfunction contributes impor-
tantly to mortality.5,6 Delirium is one of
these nonpulmonary considerations yet
remains understudied in critically ill pa-
tients. Although scoring systems for se-
verity of illness have included the
Glasgow Coma Scale7,8 as an important
predictor of outcome, there has been no
in-depth analysis focusing on the direct
contribution of delirium to clinical out-
comes in critically ill ICU patients.
Management of patients with sepsis
and multiorgan failure has tradition-
See also Patient Page.
©2004 American Medical Association. All rights reserved.
Context In the intensive care unit (ICU), delirium is a common yet underdiagnosed
form of organ dysfunction, and its contribution to patient outcomes is unclear.
Objective To determine if delirium is an independent predictor of clinical outcomes,
including 6-month mortality and length of stay among ICU patients receiving me-
chanical ventilation.
Design, Setting, and Participants Prospective cohort study enrolling 275 con-
secutive mechanically ventilated patients admitted to adult medical and coronary
ICUs of a US university-based medical center between February 2000 and May 2001.
Patients were followed up for development of delirium over 2158 ICU days using the
Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation
Scale.
Main Outcome Measures Primary outcomes included 6-month mortality, overall
hospital length of stay, and length of stay in the post-ICU period. Secondary out-
comes were ventilator-free days and cognitive impairment at hospital discharge.
Results Of 275 patients, 51 (18.5%) had persistent coma and died in the hospital.
Among the remaining 224 patients, 183 (81.7%) developed delirium at some point
during the ICU stay. Baseline demographics including age, comorbidity scores, de-
mentia scores, activities of daily living, severity of illness, and admission diagnoses were
similar between those with and without delirium (P⬎.05 for all). Patients who devel-
oped delirium had higher 6-month mortality rates (34% vs 15%, P=.03) and spent
10 days longer in the hospital than those who never developed delirium (P⬍.001).
After adjusting for covariates (including age, severity of illness, comorbid conditions,
coma, and use of sedatives or analgesic medications), delirium was independently as-
sociated with higher 6-month mortality (adjusted hazard ratio [HR], 3.2; 95% confi-
dence interval [CI], 1.4-7.7; P=.008), and longer hospital stay (adjusted HR, 2.0; 95%
CI, 1.4-3.0; P⬍.001). Delirium in the ICU was also independently associated with a
longer post-ICU stay (adjusted HR, 1.6; 95% CI, 1.2-2.3; P=.009), fewer median days
alive and without mechanical ventilation (19 [interquartile range, 4-23] vs 24 [19-
26]; adjusted P=.03), and a higher incidence of cognitive impairment at hospital dis-
charge (adjusted HR, 9.1; 95% CI, 2.3-35.3; P=.002).
Conclusion Delirium was an independent predictor of higher 6-month mortality and
longer hospital stay even after adjusting for relevant covariates including coma, seda-
tives, and analgesics in patients receiving mechanical ventilation.
JAMA. 2004;291:1753-1762 www.jama.com
Author Affiliations are listed at the end of this article. (wes.ely@vanderbilt.edu; www.icudelirium.org).
Corresponding Author: E. Wesley Ely, MD, MPH, Caring for the Critically Ill Patient Section Editor:
Division of Allergy/Pulmonary/Critical Care Medi- Deborah J. Cook, MD, Consulting Editor, JAMA.
cine, Center for Health Services Research, Sixth Floor Advisory Board: David Bihari, MD; Christian Brun-
Medical Center East #6109, Vanderbilt University Buisson, MD; Timothy Evans, MD; John Heffner, MD;
Medical Center, Nashville, TN 37232-8300 Norman Paradis, MD; Adrienne Randolph, MD.
(Reprinted) JAMA, April 14, 2004—Vol 291, No. 14 1753
DELIRIUM IN MECHANICALLY VENTILATED PATIENTS
Figure 1. Flow of Patients in Study Cohort
555 Mechanically Ventilated
Patients Admitted to
the ICU
280 Excluded
86 Had Stroke Syndrome or
Other Primary Neurologic
Disease
13 Were Deaf or Were Unable
to Speak or Understand
English
69 Were Extubated Prior
to Enrollment
27 Had Been Previously
Enrolled
41 Patient or Family
Refused to Participate
44 Died Before Study
Nurses’ Assessments
275 Enrolled
51 Persistently Comatose and
Unable to Be Evaluated for
the Primary Independent
Variable (Delirium)
224 Included in Outcomes
Analyses
ICU indicates intensive care unit.
ally been centered on dysfunction in the
heart, lungs, or kidneys rather than the
brain, though the brain is one of the or-
gans most commonly involved.9-13 De-
lirium has received little attention in
ICU settings because it is (1) rarely a
primary reason for admission, (2) of-
ten believed to be iatrogenic due to
medications, (3) frequently explained
away as “ICU psychosis,” and (4) be-
lieved to have no adverse conse-
quences in terms of patients’ ultimate
outcome.14-16 Last, there is a paucity of
published trials of prevention or treat-
ment of delirium showing altered out-
comes17 and none in ICU patients.
Even among clinicians who exhibit an
overall appreciation for delirium as an
important form of organ dysfunction, re-
cent data point to a general disconnect
between its perceived importance and
current monitoring practices. Despite re-
cent guidelines suggesting that ICU pa-
tients be monitored daily for de-
lirium,18 only 6.4% (58/912) of critical
care professionals surveyed in 2001-
2002 reported objectively monitoring for
this condition.19 Indeed, delirium, es-
1754 JAMA, April 14, 2004—Vol 291, No. 14 (Reprinted)
pecially the hypoactive subtype,20,21 goes
unrecognized in more than two thirds
of the patients in clinical practice.22-25
The original Confusion Assessment
Method of Inouye et al26 popularized
monitoring of delirium by nonpsychia-
trists. In non-ICU hospital settings, de-
lirium has been associated with pro-
longed stay, greater dependency,
subsequent institutionalization, and in-
creased mortality.17,27-34 However, only re-
cently have valid and reliable instru-
ments to measure both level of
arousal35-37 and delirium38-40 in ICU pa-
tients become available. Using these in-
struments, our pilot study showed that
delirium in the ICU was an important de-
terminant of length of hospital stay.41 We
undertook the current study to test the
hypothesis that delirium in the ICU is an
independent predictor of 6-month mor-
tality and length of stay among patients
receiving mechanical ventilation even af-
ter adjusting for other covariates.
METHODS
Patients
The Vanderbilt University institu-
tional review board approved this study,
and written informed consent was ob-
tained from patients or their surro-
gates. Enrollment criteria included any
adult, mechanically ventilated patient
admitted to medical or coronary ICUs
of the 631-bed Vanderbilt University
Medical Center between February 2000
to May 2001. While no outcomes data
from this report have been previously
published, other data from this cohort
have been published.37,39,42 Exclusion
criteria, defined a priori, are outlined
in the patient flow diagram (FIGURE 1).
Study Protocol
Study nurses enrolled patients each
morning and recorded baseline demo-
graphic information. Information col-
lected at enrollment included patient
demographics and severity of illness us-
ing the most abnormal values ob-
tained during the first 24 hours of ICU
stay to calculate Acute Physiology and
Chronic Health Evaluation II (APACHE
II) (scale range, 0-71)7 and Sequential
Organ Failure Assessment (SOFA)
©2004 American Medical Association. All rights reserved.
(scale range, 0-24) scores.8 The Charl-
son Comorbidity Index, which repre-
sents the sum of a weighted index that
takes into account the number and se-
riousness of preexisting comorbid con-
ditions, was calculated as per Deyo et
al.43 Surrogate assessments were used
for baseline activities of daily living
(scale range, 0-12),44 visual and hear-
ing deficits, and the modified Blessed
Dementia Rating Scale (mBDRS) (scale
range, 0-17), 45 an instrument vali-
dated against brain pathological speci-
mens to measure a patient’s baseline
likelihood of dementia.
Terminology
Delirium has more than 25 synonyms,
including acute encephalopathy, sep-
tic encephalopathy, toxic psychosis,
ICU psychosis, and acute confusional
state.10,11,14,46,47 Delirium will be the term
used herein, because the neurologic
monitoring instrument used in this in-
vestigation (described below) was de-
veloped and validated using Diagnos-
tic and Statistical Manual of Mental
Disorders, Fourth Edition criteria for de-
lirium.48
Explanatory Variable
Definitions and Patient Assess-
ments. Patients’ neurologic status was
assessed daily by the study nurses and
defined as normal, delirious, or coma-
tose using a 1- to 2-minute neurologic
assessment that objectively measured
patients’ arousal and delirium status.
Arousal was measured using the
Richmond Agitation-Sedation Scale
(RASS). 3 6 , 3 7 The RASS is a well-
validated and highly reliable 10-point
scale with scores from +1 to +4 as-
signed for levels of agitation through
combativeness, 0 assigned for alert and
calm state, and –1 to –5 assigned for
successive levels of depressed arousal
or coma.37 Delirium, the independent
variable, was measured using a well-
validated and highly reliable instru-
ment, the Confusion Assessment
Method for the ICU (CAM-ICU).39,40
The CAM-ICU assessment was posi-
tive if patients demonstrated an acute
change or fluctuation in the course of

their mental status (as determined by
abnormalities or fluctuations in the
RASS scores), plus inattention and
either disorganized thinking or an al-
tered level of consciousness.39,40 By defi-
nition, patients were delirious if they re-
sponded to verbal stimulation with eye
opening (RASS scores of –3 to +4) and
had positive CAM-ICU assessments. Pa-
tients were defined as comatose if they
responded only to physical/painful
stimulation with movement but had no
eye opening (RASS score, –4) or if they
had no response to verbal or physical
stimulation (RASS score, –5). Patients
were defined as normal if they were not
delirious or comatose.
Categorization by Explanatory Vari-
able. Using daily assessments de-
scribed above, it was determined a priori
that patients would be included in a “de-
lirium” group if they ever had delirium
while in the ICU, and all others would
be included in a “no delirium” group.
To understand the phenomenology of
these groups, patients in the delirium
group were further categorized as “de-
lirium only” (ie, delirium but no epi-
sodes of coma) or as “delirium-coma”
(ie, delirium and coma). Likewise, pa-
tients in the no delirium group were cat-
egorized as “normal” (ie, no episodes of
delirium or coma) or as “coma-
normal” (ie, transient coma [eg, coma
due to sedative medications] followed
by consistently normal examinations).
Patients who were comatose on all ICU
evaluations during the study were cat-
egorized as “persistent coma.”
Outcome Variables
The primary outcome variables in-
cluded 6-month mortality, overall hos-
pital length of stay, and length of stay
in the post-ICU period. In addition, we
included 2 secondary outcome vari-
ables: ventilator-free days and cogni-
tive impairment at discharge. Ventilator-
free days were defined as the number of
days alive and free of mechanical ven-
tilation between study enrollment and
day 28.49 Cognitive impairment at dis-
charge was defined as a Mini-Mental
State Examination score50 of less than 24
out of a possible 30 points.51-53
©2004 American Medical Association. All rights reserved.
DELIRIUM IN MECHANICALLY VENTILATED PATIENTS
Statistical Analysis
Patients’ baseline demographic and clini-
cal variables were assessed using Wil-
coxon rank sum tests for continuous
variables; Fisher exact tests were used
for comparing proportions. For analy-
sis of analgesics (morphine, fentanyl)
and sedatives (lorazepam, propofol),
mean daily ICU dose and cumulative
dose per patient during the ICU stay
were used as summary measures. Ad-
ministered benzodiazepines were either
lorazepam or midazolam, and mid-
azolam dose was converted to “loraze-
pam equivalents” (henceforth referred
to as lorazepam) by dividing by 3 to
achieve equipotent dose.54 Wilcoxon
rank sum tests were used to compare dis-
tributions of the drugs between the no
delirium and delirium groups.
Six-month mortality, overall hospi-
tal length of stay, and length of stay af-
ter first ICU discharge were analyzed us-
ing time-to-event analyses. Patients were
followed up from time of enrollment un-
til hospital discharge. All survivors were
then followed up using the hospital’s
electronic record system, monthly tele-
phone calls, and in-person visits for sur-
vival status. Kaplan-Meier survival
curves were used for graphical presen-
tation of time to death or hospital dis-
charge, and log-rank statistics were used
to assess difference by overall delirium
status.55 For 6-month mortality analy-
ses, patients were censored at the time
of last contact alive or at 6 months from
enrollment, whichever was first. Cen-
soring for length-of-stay analyses oc-
curred at time of hospital death.
Cox proportional hazard regression
models with time-dependent covari-
ates56-58 were used to obtain hazard ra-
tios (HRs) of death up to 6 months from
enrollment and HRs of remaining in
hospital. Details of the model construc-
tion are described below. The 11 co-
variates in the multivariable Cox
regression models included a time-
dependent coma variable, 6 additional
baseline covariates chosen a priori based
on clinical relevance (patient age at en-
rollment, Charlson Comorbidity In-
dex, 43 mBDRS score, 45 APACHE II
score, 7 SOFA score, 8,59,60 admitting
(Reprinted) JAMA, April 14, 2004—Vol 291, No. 14 1755
diagnoses of sepsis or acute respira-
tory distress syndrome), and the 4 seda-
tive and analgesic medications used in
this cohort (lorazepam, propofol, mor-
phine, and fentanyl). Patients’ neuro-
logic status (normal, delirious, coma-
tose) was updated daily in the ICU,
and time-dependent variables were
used for delirium and coma sepa-
rately. This time-dependent delirium in-
cidence variable was coded as 0 for the
days prior to the first delirious event,
and coded as 1 thereafter. The time-
dependent coma incidence variable was
coded similarly.
In addition, we performed a similar
analysis that considered the duration of
delirium using cumulative number of
days of delirium, coding the time-
dependent delirium duration variable
as 0 until a delirium event occurred, and
then incrementally adding 1 when each
additional day of delirium occurred.
The time-dependent coma duration
variable was created similarly for this
additional analysis.
The time-dependent delirium inci-
dence variable was used as the main in-
dependent variable in all Cox models
with adjustment for time-dependent
coma incidence variable. Cox regres-
sion models were then used to further
control for the additional 6 baseline co-
variates mentioned above and the 4
sedative and analgesic medications.
Dummy coding was used for missing
observations with the mBDRS. Be-
cause coma was already being handled
as a covariate in the model, the
APACHE II and SOFA scores were cal-
culated without inclusion of the
Glasgow Coma Scale. To incorporate
sedative (lorazepam, propofol) and an-
algesic (morphine, fentanyl) medica-
tions in a time-dependent fashion, daily
use of medication was coded as 1 for
each of 4 drug variables separately if any
amount was administered prior to daily
assessment of neurologic status and was
coded as 0 otherwise. In an additional
analysis, time-dependent cumulative
dose of sedatives and narcotics were in-
corporated into the model. Collinear-
ity among all independent variables was
evaluated by examining the variance in-
DELIRIUM IN MECHANICALLY VENTILATED PATIENTS
Figure 2. Daily Neurologic Status of 275 Patients in the ICU, Through the First 14 Days of the Study
Normal
60
50
40
Percentage
30
20
10
0
1 3 5 7 9 11
Days After Enrollment
Denominator is identical (N = 275) for all 14 days. ICU indicates intensive care unit.
flation factor.61 Assumptions of pro-
portional hazard for the final models
were evaluated by examining interac-
tions between time and each variable
in the model. When significant inter-
actions were found, those interaction
terms were included in the final model.
Ventilator-free days were calculated
as described in the “Dependent Vari-
ables” section above and compared be-
tween the delirium and no delirium
groups. A Poisson regression model
with overdispersion correction was used
to control for the set of covariates stated
above. Presence or absence of cogni-
tive impairment at hospital discharge
was assessed as described in the “De-
pendent Variables” section and com-
pared between the delirium and no de-
lirium groups using Fisher exact tests,
and a logistic regression model was used
to adjust for the set of 11 covariates. All
data analyses were performed using SAS
8.02 (SAS Institute, Cary, NC); a sig-
nificance level of .05 was used for sta-
tistical inferences.
RESULTS
Patients’ Baseline Characteristics
During the study period, 555 mechani-
cally ventilated ICU patients were ad-
mitted, of whom 275 (49.5%) were en-
rolled within a mean and median of 1
day and 280 met exclusion criteria (Fig-
ure 1). On enrollment, 23 (8.4%) pa-
tients were defined as normal, 89
(32.4%) as delirious, and 163 (59.3%)
as comatose. FIGURE 2 shows the pro-
portion of patients in each neurologic
1756 JAMA, April 14, 2004—Vol 291, No. 14 (Reprinted)
Delirium Coma
13 1 3 5 7 9 11 13 1 3 5 7 9 11 13
Days After Enrollment Days After Enrollment
category (as well as death or ICU dis-
charge) over the first 14 days from study
enrollment. Of the 275 enrolled pa-
tients, 51 (18.5%) never woke up from
coma and experienced 100% ICU mor-
tality after a median of 3 (interquartile
range [IQR], 1-5) days. These 51 pa-
tients with persistent coma had a mean
age of 55 (SD, 16) years and similar
baseline characteristics compared with
the remaining 224 patients, with the ex-
ception of greater severity of illness at
enrollment as measured by mean
APACHE II scores (29.5 [SD, 9]) and
SOFA scores (12.1 (SD, 3.8]) and by
greater rates of malignancy (14%) and
sepsis/acute respiratory distress syn-
drome (63%) as admission diagnoses
(P⬍.05 for all). Due to their 100% mor-
tality and the inability to evaluate them
for the independent variable (delirium),
patients categorized as experiencing
persistent coma were not included in
outcomes analyses. The remaining 224
patients were used for these analyses;
their baseline characteristics are shown
in TABLE 1. The cohort was divided into
2 groups according to whether they ever
developed delirium in the ICU. There
were no significant differences be-
tween the delirium and no delirium
groups for demographic variables, base-
line comorbidities, activities of daily liv-
ing, severity-of-illness scores, organ dys-
function scores, or admission diagnoses.
Prevalence of Delirium and Coma
All 224 patients were followed up for de-
velopment of delirium over 2158 ICU
©2004 American Medical Association. All rights reserved.
Discharged From ICU Death
1 3 5 7 9 11 13 1 3 5 7 9 11 13
Days After Enrollment Days After Enrollment
days. Forty-one patients (18.3%) never
demonstrated delirium in the ICU (ie,
the no delirium group); of those, 24
(58.5%) were in a coma for a median of
1.5 (IQR, 1-3) days, during which time
21 (87.5%) received sedative or analge-
sic medications. Delirium in the ICU de-
veloped in 183 (81.7%) patients (ie, the
delirium group) for a median of 2 (IQR,
1-3) days, of whom 123 also were in a
coma for a median of 2 (IQR, 1-4) days.
Delirium occurred in 77.9% (60/77) of
those without coma and in 83.7% (123/
147) of those with coma (P=.29). Over-
all, patients spent 21.6% of their ICU
days as normal, 43.1% as delirious, and
35.3% as comatose. Of patients who
were alert or easily arousable as mea-
sured by a RASS score of 0 or −1, more
than half (54.5%) were delirious.
Sedative and Analgesic
Medication Use
Mean daily dose and cumulative ad-
ministered dose of sedative and nar-
cotic medications (ie, lorazepam, pro-
pofol, morphine, and fentanyl) used in
this cohort are presented in TABLE 2.
Both mean daily and cumulative doses
of these medications were higher in pa-
tients in the delirium group, but only
lorazepam was significantly different be-
tween the 2 groups.
Delirium and Associated
Clinical Outcomes
Six-Month Mortality. During the
6-month follow-up period, 34% (63/
183) of the patients in the delirium group
 DELIRIUM IN MECHANICALLY VENTILATED PATIENTS

died vs 15% (6/41) of the patients in the hospital overall (Table 3). FIGURE 4A hospital stay, patients diagnosed with de-
no delirium group (P=.03) (TABLE 3). shows Kaplan-Meier curves of the prob- lirium had an adjusted risk of remain-
FIGURE 3A shows Kaplan-Meier curves ability of remaining in the hospital ac- ing in the hospital that was twice as high
of survival to 6 months among the pa- cording to the clinical distinction of no as those who never developed delirium
tients in both groups, with significantly delirium vs delirium. Figure 4B shows and a 60% greater risk of remaining in
higher mortality among patients with de- the no delirium and delirium groups fur- the wards after ICU discharge (Table 3).
lirium in the ICU. Figure 3B further de- ther categorized by coma status, as in In a separate analysis, time-dependent
picts the patients’ survival according to Figure 3B. At any given time during the cumulative doses of sedatives and nar-
both delirium and coma status.
Using a time-dependent multivari- Table 1. Baseline Characteristics of the Patients*
able Cox proportional hazards model No. (%)†
to adjust for all 11 of the covariates (in-
No Delirium Delirium
cluding coma incidence and adminis- Characteristic (n = 41) (n = 183)
tration of sedative and analgesic Age, mean (SD), y 54 (17) 56 (17)
medications), delirium was associated Men 18 (44) 95 (52)
with a more than 3-times higher risk Race
of dying by 6 months (Table 3). In an White 32 (78) 145 (79)
additional analysis (data not shown), Black 9 (22) 38 (21)
time-dependent cumulative doses of Charlson Comorbidity Index, mean (SD) 3.2 (2.8) 3.2 (2.8)
sedatives and narcotics were incorpo- Vision deficits, No./total (%)‡ 23/33 (70) 104/153 (68)
rated into the model, with similar re- Hearing deficits, No./total (%)‡ 5/32 (16) 29/152 (19)
sults compared with the primary analy- mBDRS score, mean (SD) 0.14 (0.6) 0.23 (0.8)
sis. No collinearity was identified Activities of daily living, mean (SD) 0.81 (2.4) 0.91 (2.3)
among the covariates used in these APACHE II score, mean (SD) 23.2 (9.6) 25.6 (8.1)
analyses (all variance inflation factors SOFA score, mean (SD) 9.5 (2.9) 9.6 (3.4)
were ⱕ2, well below the threshold ICU admission diagnosis§
Sepsis and/or acute respiratory distress syndrome 24 (59) 78 (43)
of 10 used to indicate potential Pneumonia 6 (15) 35 (19)
collinearity). To complement the mor- Myocardial infarction/congestive heart failure 4 (10) 15 (8)
tality analysis presented in Table 3, a Hepatic or renal failure 0 11 (6)
similar analysis that considered the du- Chronic obstructive pulmonary disease 2 (5) 18 (10)
ration of delirium found that after ad- Gastrointestinal bleeding 2 (5) 18 (10)
justing for the covariates, each addi- Malignancy 0 7 (4)
tional day an ICU patient spent in Drug overdose 3 (7) 8 (4)
delirium was associated with a 10% in- Other 14 (34) 53 (29)
creased risk of death (HR, 1.1; 95% con- Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; mBDRS, modi-
fidence interval [CI], 1.0-1.3; P = .03). fied Blessed Dementia Rating Scale; SOFA, Sequential Organ Failure Assessment.
*All comparisons between the no delirium and delirium groups were nonsignificant (P⬎.05). See “Methods” section for
Hospital Lengths of Stay. Com- descriptions of scales and for scale ranges.
†Except where noted otherwise.
pared with patients in the no delirium ‡Denominators indicate number of patients with available information.
group, those who did develop delirium §Recorded by the patients’ medical team as the diagnoses most representative of the reason for admission to the ICU.
Patients were sometimes given more than 1 admission diagnosis by the medical team, resulting in column totals
spent a median of 10 days longer in the ⬎100%.

Table 2. Daily and Cumulative Doses of Sedative and Analgesic Medications

Daily ICU Dose, Mean (SD), mg Cumulative ICU Dose, Mean (SD), mg*

No Delirium Delirium No Delirium Delirium

Drug (n = 41) (n = 183) P Value† (n = 41) (n = 183) P Value†
Lorazepam 1.12 (2.2) 4.8 (12.8) .01 9.0 (20.0) 49.2 (131.3) .001
Propofol 36.6 (258.6) 48.4 (172.9) .19 362.1 (1265.4) 591.2 (3942.2) .20
Morphine 5.8 (17.0) 17.3 (163.8) .79 48.0 (147.0) 168.1 (1321.9) .66
Fentanyl 0.53 (1.7) 0.78 (1.7) .22 3.1 (10.3)‡ 8.7 (22.9)‡ .12
Abbreviation: ICU, intensive care unit.
*In the persistently comatose patients, the mean (SD) cumulative doses of these medications were: lorazepam, 15 (27) mg; propofol, 318 (1434) mg; morphine, 107 (345) mg; and
fentanyl, 3 (12) mg.
†By Wilcoxon rank sum test for no delirium vs delirium.
‡Fentanyl is commonly reported to be 100 times more potent than morphine.54 Therefore, using a dose conversion factor of 0.01, the median cumulative “morphine equivalent”
dose of fentanyl given to patients in the no delirium and delirium groups would equate to 310 mg and 870 mg, respectively. While this mathematical conversion may be flawed
or confounded in vivo, such large values are plausible considering fentanyl’s initially short duration of action,18 the potential for rapid tolerance to fentanyl,62-64 and the adminis-
tration of fentanyl as a continuous infusion rather than an intermittent bolus.

©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, April 14, 2004—Vol 291, No. 14 1757
DELIRIUM IN MECHANICALLY VENTILATED PATIENTS

cotics were incorporated into the model of remaining in the hospital or in the tor among patients in the delirium group
with similar results (data not shown) wards, respectively (hospital length of (median, 19; IQR, 4-23) vs those in the
compared with the primary analysis. To stay: adjusted HR, 1.2; 95% CI, 1.1-1.3; no delirium group (median, 24; IQR, 19-
complement the length-of-stay analy- P = .002; post-ICU length of stay: ad- 26) (P⬍.001). After adjusting for the 11
ses presented in Table 3, similar analy- justed HR, 1.1; 95% CI, 1.0-1.2; P=.04). covariates, this difference remained sig-
ses that considered the duration of de- Secondary Outcomes. Secondary nificant (P = .03). Cognitive assess-
lirium found that after adjusting for the outcomes included ventilator-free days ments were not available at the time of
covariates, each additional day spent in in the ICU and neurologic impairment hospital discharge for 51 of 179 survi-
delirium by an ICU patient was associ- at discharge. There were significantly vors, due either to inability to complete
ated with a 20% and a 10% increased risk fewer days alive and free of the ventila- testing or to unexpected discharge. One
hundred twenty-eight survivors were
Table 3. Delirium Status and Clinical Outcomes Including 6-Month Mortality and Lengths of
tested, of whom 63 (49.2%) had dis-
Stay charge cognitive impairment as defined
No Delirium Delirium Adjusted P Value in the “Methods” section. Of those tested,
6-Month Mortality twice as many patients in the delirium
No. 41 183 group vs the no delirium group exhib-
Rate, No. (%) 6 (15) 63 (34) ited cognitive impairment at hospital dis-
Adjusted HR (95% CI)* Reference 3.2 (1.4-7.7) .008 charge (54.9% [56/102] vs 26.9% [7/26],
Hospital Stay
respectively; P=.01), and multivariable
No. 41 183 analysis revealed that the patients in the
Median (IQR), d 11 (7-14) 21 (19-25) delirium group were 9 times more likely
Adjusted HR (95% CI)* Reference 2.0 (1.4-3.0) ⬍.001 to be discharged with cognitive impair-
Post-ICU Stay†
ment than were those in the no de-
No. 40 156
lirium group (adjusted HR, 9.1; 95% CI,
Median (IQR), d 5 (2-7) 7 (4-15.5)
2.3-35.3; P=.002).
Adjusted HR (95% CI)* Reference 1.6 (1.1-2.3) .009
Abbreviations: CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; IQR, interquartile range. COMMENT
*Multivariable model incorporating baseline covariates including patient age at enrollment, Charlson Comorbidity In-
dex,43 modified Blessed Dementia Rating Scale score,45 Acute Physiology and Chronic Health Evaluation II (APACHE The development of delirium in these
II) score,7 Sequential Organ Failure Assessment (SOFA) score,59,60 admitting diagnoses of sepsis or acute respiratory mechanically ventilated patients was as-
distress syndrome, and time-varying covariates for coma and use (yes/no) of lorazepam, propofol, morphine, and
fentanyl. Assumptions of proportional hazard for the final models were evaluated by examining interactions between sociated with a 3-fold increase in risk of
time and each variable in the model. Interaction terms were included in the model whenever nonproportionality of
hazards was observed. For analysis of hospital length of stay, interactions were detected between time and APACHE death after controlling for preexisting co-
II scores, SOFA scores, presence of coma, and use of lorazepam. No other significant interactions were observed.
†Twenty-eight patients died in the ICU (1 in the no delirium group and 27 in the delirium group, P = .03) and were
morbidities, severity of illness, coma, and
therefore not included in the post-ICU length-of-stay analysis. the use of sedative and analgesic medi-

Figure 3. Kaplan-Meier Analysis of Delirium in the Intensive Care Unit and 6-Month Survival

A B
100 100
90 90
80 80
Probability of Survival, %

Probability of Survival, %

70 70
60 60
50 50
40 40
30 30
No Delirium Delirium
20 20
No Delirium Normal Delirium Only
10 Delirium 10 Coma-Normal Delirium-Coma
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Months After Enrollment Months After Enrollment
No. at Risk No. at Risk
No Delirium 41 34 28 25 22 21 19 No Delirium
Delirium 183 138 116 111 104 98 88 Normal 17 15 11 11 10 10 10
Coma-Normal 24 19 17 15 12 11 9
Delirium
Delirium Only 60 51 42 39 34 33 29
Delirium-Coma 123 87 74 72 70 65 59

1758 JAMA, April 14, 2004—Vol 291, No. 14 (Reprinted) ©2004 American Medical Association. All rights reserved.
 DELIRIUM IN MECHANICALLY VENTILATED PATIENTS

cations. While development of coma is .icudelirium.org). We have found dur- termination of modifiable risk factors
well recognized as a risk factor for ing a year-long implementation study for delirium in the ICU. Numerous risk
death,7,8,10,11 this investigation is the first incorporating more than 22 000 pa- factors for delirium have been identi-
to document a strong relationship be- tient observations that nursing staff fied, including preexisting cognitive im-
tween delirium and clinical outcomes af- readily incorporated such measure- pairment; advanced age; use of psycho-
ter adjusting for coma. These data ments into routine care,67 in keeping active drugs; mechanical ventilation;
showed not only that ever developing with recently issued guidelines of the untreated pain; and a variety of medi-
this type of organ dysfunction was a pre- Society of Critical Care Medicine.18 cal conditions such as heart failure, pro-
dictor of death by 6 months after ICU Perhaps the greatest benefit of incor- longed immobilization, abnormal blood
discharge, but also that the number of porating delirium monitoring would be pressure, anemia, sleep deprivation, and
days spent in a delirious state pre- the enhanced detection of the hypoac- sepsis.17,34,71-81
dicted mortality. In addition, delirium tive delirium subtype, often called “quiet” Some of the most readily imple-
was not simply a transition state from delirium because it is characterized by mented opportunities for improving
coma to normal, as delirium occurred a flat affect or apathy and often present care could be to correct brain ischemia/
just as often among those who never de- in otherwise calm and seemingly alert pa- hypoxemia,82 to modify the adminis-
veloped coma as it did among those who tients.68 This is in contrast to the readily tration of psychoactive medications,78
did develop coma at some stage, and per- detected hyperactive delirium that is and to aggressively treat both under-
sisted in 11% of patients at the time of characterized by agitation, restlessness, lying infection and the manifestations
hospital discharge. attempting to remove catheters or tubes, of severe sepsis, especially in elderly pa-
hitting, biting, and emotional lability.68 tients.11,17,83-86 Regarding hypoxemia,
Monitoring for Delirium in the ICU In this study, hypoactive delirium was Hopkins et al82 found in 55 mechani-
In the absence of data linking de- present in over 50% of patients with nor- cally ventilated patients with acute lung
lirium to outcomes, few ICUs rou- mal or near-normal arousal. This type of injury that mean oxygen saturations
tinely monitor for delirium. Monitor- brain dysfunction may portend a worse were below 90% for 122 hours and be-
ing for delirium with the CAM-ICU, prognosis than hyperactive delirium, ac- low 85% for 13 hours per patient. Re-
which is easily incorporated by nurses counts for the majority of delirium ob- garding use of psychoactive drugs, re-
into their daily work and takes only 1 servations, and is the most commonly cent studies 87-89 have shown that
to 2 minutes, could allow the medical missed subtype of delirium.21,47,68-70 reducing unnecessary use of sedatives
team to consider causes and modifica- and analgesics may improve patients’
tions in their treatment of the patient Potentially Modifiable Risk Factors outcomes. Another approach to inter-
experiencing this organ dysfunc- Our findings suggest that an impor- vention would be to treat delirious pa-
tion65,66 (downloadable materials and tant opportunity for improving the care tients with procognitive medications
discussion available at http://www of critically ill patients may be the de- such as haloperidol, as recommended

Figure 4. Kaplan-Meier Analysis of Delirium in the Intensive Care Unit and Hospital Length of Stay

A B
100 100
Probability of Being in the Hospital, %

Probability of Being in the Hospital, %

No Delirium No Delirium
90 Delirium 90
Normal
80 80 Coma-Normal
70 70 Delirium
Delirium Only
60 60
Delirium-Coma
50 50
40 40
30 30
20 20
10 10
0 0
0 10 20 30 40 50 60 0 10 20 30 40 50 60
Days After Enrollment Days After Enrollment
No. at Risk No. at Risk
No Delirium 41 23 8 3 3 1 0 No Delirium
Delirium 183 137 82 43 20 13 4 Normal 17 8 3 2 2 1 0
Coma-Normal 24 15 5 1 1 0 0
Delirium
Delirium Only 60 38 25 17 8 5 2
Delirium-Coma 123 99 57 26 12 8 2

©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, April 14, 2004—Vol 291, No. 14 1759
DELIRIUM IN MECHANICALLY VENTILATED PATIENTS
by the Society of Critical Care Medi-
cine guidelines.18 However, such inter-
ventions need to be tested in future re-
search. Our multivariable analysis did
demonstrate that delirium influenced
outcomes even after adjusting for these
medications.89 Thus, the development
of delirium was of clinical relevance
above and beyond that attributed to iat-
rogenic administration of sedative and
analgesic medications.
Long-term Cognitive Impairment
At the time of hospital discharge, there
was substantial cognitive impairment in
1 out of every 2 survivors tested, which
was significantly more common among
patients who ever developed delirium
compared with those who did not. An
important limitation regarding this ob-
servation is that the patients were not
tested for the presence of preexisting (ie,
prior to ICU admission) cognitive im-
pairment (a problem not easily re-
solved due to the emergent nature of
these patients’ illnesses). However, we
did use a well-validated surrogate assess-
ment of dementia to estimate and ad-
just for this possible confounder.
While long-term neuropsychological
impairment following mechanical ven-
tilation is now recognized with increas-
ing frequency,42,82 its relationship with
delirium during ICU stay is not known
and deserves further study. Ongoing de-
lirium has been observed by others, in-
cluding Levkoff et al,32 who found that
the majority of hospitalized elderly pa-
tients did not experience complete reso-
lution of delirium symptoms prior to dis-
charge. More recently, McNicoll and
colleagues90 reported that 40% of older
ICU patients had ongoing delirium dur-
ing the post-ICU period, and Kiely et al91
found that almost 20% of elderly pa-
tients had delirium at the time of admis-
sion to postacute facilities.
Limitations and Future Directions
Four limitations of this study should be
noted. The first limitation has to do with
the delirium coding and the fact that
study protocol mandated only once-
daily CAM-ICU assessments. Assess-
ing patients more often with the
1760 JAMA, April 14, 2004—Vol 291, No. 14 (Reprinted)
CAM-ICU will help to improve our
understanding of the phenomenology
of delirium in these patients. In the
year-long implementation study men-
tioned above, 67 nurses adopted de-
lirium monitoring so readily that they
assessed patients more often than the
twice-daily requirement. Our coding of
patients as having or not having de-
lirium for a given day has to do with
the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition defi-
nition of this disorder. However, it is
important to remember that delirium,
by definition, fluctuates over time. Due
to the fluctuating nature of this disor-
der, it is considered present until cleared
for 24 hours. It would be feasible to
code the patients in 12-hour intervals.
Even using such a schema, the de-
lirium “episode” will be considered as
ongoing until there are 2 consecutive
12-hour shifts with negative CAM-
ICU assessments. Second, we did not
examine the impact from the broad
range of psychoactive medications
other than sedatives and analgesics, pa-
tients’ pharmacological interindi-
vidual variability in transport and me-
tabolism of medications, or genetic
predisposition to this form of brain in-
jury. Third, while our cohort did in-
corporate a broad range of diagnoses in
the medical ICU population, other types
of critically ill patients should be in-
vestigated, including patients in trauma
and surgical ICUs as well as those with
baseline neurologic comorbidities.
Lastly, this observational study was
not designed to prove a cause-and-
effect relationship between delirium
and clinical outcomes. However, there
are data to support a pathophysiologic
rationale for the brain as a potentiator
(rather than merely a marker) of total-
body injury during critical illness. The
brain responds to systemic infections
and injury with an inflammatory
response of its own that also includes
the production of cytokines, cell
infiltration, and tissue damage. 92,93
Reports also indicate that local inflam-
mation in the brain and subsequent
activation of the central nervous sys-
tem’s immune responses are accompa-
©2004 American Medical Association. All rights reserved.
nied by peripheral manifestations of
systemic inflammation, including pro-
duction of large amounts of peripher-
ally produced tumor necrosis factor ␣,
interleukin 1, and interferon ␦.92,94-96
Such centrally mediated inflammation
could influence the development or
resolution of multiple organ dysfunc-
tion syndrome. Direct injury to the
central nervous system induced by
intracerebral endotoxin has also been
shown to result in loss of the liver’s
ability to metabolize drugs indepen-
dent of intraperitoneally administered
endotoxin.97-99 Thus, the brain pro-
duces its own signaling that likely
influences the overall outcome of the
patient. The exact nature of the signal-
ing between the brain and other sys-
temic organs remains to be elucidated.
In the meantime, this study has dem-
onstrated an important clinical asso-
ciation as well as the need for further
examination, including etiologic and
interventional studies.
CONCLUSIONS
In this single-center observational
study, we found that delirium among
mechanically ventilated patients in the
ICU was associated with higher
6-month mortality and longer lengths
of stay even after adjusting for numer-
ous covariates. This study raises the
question of how diligently delirium
should be monitored in acutely ill
patients, especially considering that
validated instruments can be imple-
mented with a high degree of repro-
ducibility and rates of compliance at the
bedside by those routinely caring for pa-
tients in the ICU. Some recent system-
atic reviews of sedation practices and
their consequences in the ICU have not
mentioned delirium,100,101 while oth-
ers have suggested that missing de-
lirium in acutely ill patients should be
considered a medical error.25 Future
studies are needed to determine
whether prevention or treatment of de-
lirium would change clinical out-
comes including mortality, length of
stay, cost of care, and long-term neu-
ropsychological outcomes among sur-
vivors of critical illness.

Author Affiliations: Department of Medicine, Divi-
sion of General Internal Medicine and Center for Health
Services Research and the Veterans Affairs Tennes-
see Valley Geriatric Research, Education and Clinical
Center (GRECC) (Drs Ely, Shintani, Speroff, Gordon,
Inouye, Dittus, and Ms Truman), Division of Allergy/
Pulmonary/Critical Care Medicine (Drs Ely
and Bernard, Ms Truman), Department of Biostatis-
tics (Drs Shintani, Speroff, and Harrell), and Depart-
ment of Psychiatry (Dr Gordon), Vanderbilt Univer-
sity School of Medicine, Nashville, Tenn; and
Department of Medicine, Yale University School of
Medicine, New Haven, Conn (Dr Inouye)
Author Contributions: Drs Ely, Shintani, Speroff, and
Dittus and Ms Truman had full access to the all of the
data in the study and take responsibility for the integ-
rity of the data and the accuracy of the data analyses.
Study concept and design: Ely, Shintani, Truman,
Gordon, Bernard, Dittus.
Acquisition of data: Ely, Truman.
Analysis and interpretation of data: Ely, Shintani,
Truman, Speroff, Gordon, Harrell, Inouye, Bernard,
Dittus.
Drafting of the manuscript: Ely, Shintani, Truman.
Critical revision of the manuscript for important in-
tellectual content: Ely, Truman, Speroff, Gordon,
Harrell, Inouye, Bernard, Dittus.
Statistical expertise: Ely, Shintani, Speroff, Harrell,
Dittus.
Obtained funding; study supervision: Ely, Bernard,
Dittus.
Administrative, technical, or material support: Ely,
Truman, Gordon, Inouye, Bernard, Dittus.
Funding/Support: Dr Ely is a recipient of the Paul Bee-
son Faculty Scholar Award from the Alliance for Ag-
ing Research and of a K23 from the National Insti-
tutes of Health (AG01023-01A1) and the Veterans
Affairs Tennessee Valley Geriatric Research, Educa-
tion, and Clinical Center. Dr Inouye is a recipient of a
Midcareer Award (K24AG00949) from the National
Institute on Aging and a Donaghue Investigator Award
(DF98-105) from the Patrick and Catherine Weldon
Donaghue Medical Research Foundation.
Role of the Sponsor: The Alliance for Aging Re-
search, National Institutes of Health, National Insti-
tute on Aging, and the Patrick and Catherine Wel-
don Donaghue Medical Research Foundation had no
role in the design or conduct of the study; in the col-
lection, management, analysis, or interpretation of the
data; or in the preparation, review, or approval of the
manuscript.
Acknowledgment: We thank all of the dedicated and
open-minded ICU staff and Meredith Gambrell, who
contributed to this work. In addition, we thank Geeta
Mehta, MD; Derek Angus, MB, MPH; Craig Wein-
ert, MD, MPH; and Jean-Louis Vincent, MD, PhD, who
provided important early feedback on the manu-
script.
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